tbuckley/cabot-search huggingface dataset:
Patient-Reported Functional Impairment Due to Hearing Loss and Tinnitus After Cisplatin-Based Chemotherapy
Authors: Victoria A. Sanchez, Megan M. Shuey, Paul C. Dinh, Patrick O. Monahan, Sophie D. Fosså, Howard D. Sesso, M. Eileen Dolan, Lawrence H. Einhorn, David J. Vaughn, Neil E. Martin, Darren R. Feldman, Kurt Kroenke, Chunkit Fung, Robert D. Frisina, Lois B. Travis
Journal: Journal of Clinical Oncology (2023)

Cisplatin is widely used and highly ototoxic, but patient-reported functional impairment because of cisplatin-related hearing loss (HL) and tinnitus has not been comprehensively evaluated.
Inherited mutations in Chinese patients with upper tract urothelial carcinoma
Authors: Junlong Wu, Shengming Jin, Chengyuan Gu, Yu Wei, Yao Zhu, Andrea Necchi, Shahrokh F Shariat, Jian Pan, Hualei Gan, Bo Dai, Hailiang Zhang, Guohai Shi, Yu Zhu, Yijun Shen, Yiping Zhu, Dingwei Ye
Journal: Cell Reports Medicine (2023)

Upper tract urothelial carcinoma (UTUC) accounts for 10% of urothelial carcinomas (UCs) and has a substantial hereditary component. However, the majority of our knowledge of germline spectrum comes from bladder cancer (BCa) data in White populations. Here, we sequence 309 Chinese UTUC cases and identify 71 germline pathogenic/likely pathogenic (P/LP) mutations in 62 patients (20.1%). Compared with White cases, we observe disparities and similarities in inherited mutational profiles. Association analysis reveals that germline P/LP mutations in MSH2, BRCA2, BRCA1, and BRIP1 significantly increase UTUC risk in Chinese populations. Furthermore, germline P/LP mutation in homologous recombination genes indicates poor prognosis for non-metastatic UTUC. Finally, we perform paired sequencing and observe significant correlations between germline mutation patterns and tumor subtypes. This study highlights the importance of genetic testing in patients with UTUC and calls for germline data from various ethnicities to better understand this disease.
Novel discovery of schisandrin A regulating the interplay of autophagy and apoptosis in oligoasthenospermia by targeting SCF/c-kit and TRPV1 via biosensors
Authors: Lijuan Ma, Boyi Li, Jinchen Ma, Chunyuan Wu, Nan Li, Kailin Zhou, Yun Yan, Mingshuang Li, Xiaoyan Hu, Hao Yan, Qi Wang, Yanfei Zheng, Zhisheng Wu
Journal: Acta Pharmaceutica Sinica B (2023)

Oligoasthenospermia is the primary cause of infertility. However, there are still enormous challenges in the screening of critical candidates and targets of oligoasthenospermia owing to its complex mechanism. In this study, stem cell factor (SCF), c-kit, and transient receptor potential vanilloid 1 (TRPV1) biosensors were successfully established and applied to studying apoptosis and autophagy mechanisms. Interestingly, the detection limit reached 2.787 × 10-15 g/L, and the quantitative limit reached 1.0 × 10-13 g/L. Furthermore, biosensors were used to investigate the interplay between autophagy and apoptosis. Schisandrin A is an excellent candidate to form a system with c-kit similar to SCF/c-kit with a detection constant (KD) of 5.701 × 10-11 mol/L, whereas it had no affinity for SCF. In addition, it also inhibited autophagy in oligoasthenospermia through antagonizing TRPV1 with a KD of up to 4.181 × 10-10 mol/L. In addition, in vivo and in vitro experiments were highly consistent with the biosensor. In summary, high-potency schisandrin A and two potential targets were identified, through which schisandrin A could reverse the apoptosis caused by excessive autophagy during oligoasthenospermia. Our study provides promising insights into the discovery of effective compounds and potential targets via a well-established in vitro-in vivo strategy.
Brief structured respiration practices enhance mood and reduce physiological arousal
Authors: Melis Yilmaz Balban, Eric Neri, Manuela M. Kogon, Lara Weed, Bita Nouriani, Booil Jo, Gary Holl, Jamie M. Zeitzer, David Spiegel, Andrew D. Huberman
Journal: Cell Reports Medicine (2023)

Controlled breathwork practices have emerged as potential tools for stress management and well-being. Here, we report a remote, randomized, controlled study (NCT05304000) of three different daily 5-min breathwork exercises compared with an equivalent period of mindfulness meditation over 1 month. The breathing conditions are (1) cyclic sighing, which emphasizes prolonged exhalations; (2) box breathing, which is equal duration of inhalations, breath retentions, and exhalations; and (3) cyclic hyperventilation with retention, with longer inhalations and shorter exhalations. The primary endpoints are improvement in mood and anxiety as well as reduced physiological arousal (respiratory rate, heart rate, and heart rate variability). Using a mixed-effects model, we show that breathwork, especially the exhale-focused cyclic sighing, produces greater improvement in mood (p < 0.05) and reduction in respiratory rate (p < 0.05) compared with mindfulness meditation. Daily 5-min cyclic sighing has promise as an effective stress management exercise.
Advanced subunit vaccine delivery technologies: From vaccine cascade obstacles to design strategies
Authors: Yingying Hou, Min Chen, Yuan Bian, Xi Zheng, Rongsheng Tong, Xun Sun
Journal: Acta Pharmaceutica Sinica B (2023)

Designing and manufacturing safe and effective vaccines is a crucial challenge for human health worldwide. Research on adjuvant-based subunit vaccines is increasingly being explored to meet clinical needs. Nevertheless, the adaptive immune responses of subunit vaccines are still unfavorable, which may partially be attributed to the immune cascade obstacles and unsatisfactory vaccine design. An extended understanding of the crosstalk between vaccine delivery strategies and immunological mechanisms could provide scientific insight to optimize antigen delivery and improve vaccination efficacy. In this review, we summarized the advanced subunit vaccine delivery technologies from the perspective of vaccine cascade obstacles after administration. The engineered subunit vaccines with lymph node and specific cell targeting ability, antigen cross-presentation, T cell activation properties, and tailorable antigen release patterns may achieve effective immune protection with high precision, efficiency, and stability. We hope this review can provide rational design principles and inspire the exploitation of future subunit vaccines.
Full-profile pharmacokinetics, anticancer activity and toxicity of an extended release trivalent PEGylated irinotecan prodrug
Authors: Shiwen Song, Dong Sun, Hong Wang, Jinliang Wang, Huijing Yan, Xuan Zhao, John Paul Fawcett, Xin Xu, Deqi Cai, Jingkai Gu
Journal: Acta Pharmaceutica Sinica B (2023)

Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite, SN-38. Unfortunately, the limited utility of irinotecan is attributed to its pH-dependent stability, short half-life and dose-limiting toxicity. To address this problem, a novel trivalent PEGylated prodrug (PEG-[Irinotecan]3) has been synthesized and its full-profile pharmacokinetics, antitumor activity and toxicity compared with those of irinotecan. The results show that after intravenous administration to rats, PEG-[Irinotecan]3 undergoes stepwise loss of irinotecan to form PEG-[Irinotecan]3‒x (x = 1,2) and PEG-[linker] during which time the released irinotecan undergoes conversion to SN-38. As compared with conventional irinotecan, PEG-[Irinotecan]3 displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and half-life. In a colorectal cancer-bearing model in nude mice, the tumor concentrations of irinotecan and SN-38 produced by PEG-[Irinotecan]3 were respectively 86.2 and 2293 times higher at 48 h than produced by irinotecan. In summary, PEG-[Irinotecan]3 displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than irinotecan. This supports the view that PEG-[Irinotecan]3 is a superior anticancer drug to irinotecan and it has entered the phase II trial stage.
Gestational diabetes is driven by microbiota-induced inflammation months before diagnosis
Authors: Yishay Pinto, Sigal Frishman, Sondra Turjeman, Adi Eshel, Meital Nuriel-Ohayon, Oshrit Shtossel, Oren Ziv, William Walters, Julie Parsonnet, Catherine Ley, Elizabeth L Johnson, Krithika Kumar, Ron Schweitzer, Soliman Khatib, Faiga Magzal, Efrat Muller, Snait Tamir, Kinneret Tenenbaum-Gavish, Samuli Rautava, Seppo Salminen, Erika Isolauri, Or Yariv, Yoav Peled, Eran Poran, Joseph Pardo, Rony Chen, Moshe Hod, Elhanan Borenstein, Ruth E Ley, Betty Schwartz, Yoram Louzoun, Eran Hadar, Omry Koren
Journal: Gut (2023)

Objective Gestational diabetes mellitus (GDM) is a condition in which women without diabetes are diagnosed with glucose intolerance during pregnancy, typically in the second or third trimester. Early diagnosis, along with a better understanding of its pathophysiology during the first trimester of pregnancy, may be effective in reducing incidence and associated short-term and long-term morbidities. Design We comprehensively profiled the gut microbiome, metabolome, inflammatory cytokines, nutrition and clinical records of 394 women during the first trimester of pregnancy, before GDM diagnosis. We then built a model that can predict GDM onset weeks before it is typically diagnosed. Further, we demonstrated the role of the microbiome in disease using faecal microbiota transplant (FMT) of first trimester samples from pregnant women across three unique cohorts. Results We found elevated levels of proinflammatory cytokines in women who later developed GDM, decreased faecal short-chain fatty acids and altered microbiome. We next confirmed that differences in GDM-associated microbial composition during the first trimester drove inflammation and insulin resistance more than 10 weeks prior to GDM diagnosis using FMT experiments. Following these observations, we used a machine learning approach to predict GDM based on first trimester clinical, microbial and inflammatory markers with high accuracy. Conclusion GDM onset can be identified in the first trimester of pregnancy, earlier than currently accepted. Furthermore, the gut microbiome appears to play a role in inflammation-induced GDM pathogenesis, with interleukin-6 as a potential contributor to pathogenesis. Potential GDM markers, including microbiota, can serve as targets for early diagnostics and therapeutic intervention leading to prevention.
Genomic repertoires linked with pathogenic potency of arthritogenic<i>Prevotella copri</i>isolated from the gut of patients with rheumatoid arthritis
Authors: Takuro Nii, Yuichi Maeda, Daisuke Motooka, Mariko Naito, Yuki Matsumoto, Takao Ogawa, Eri Oguro-Igashira, Toshihiro Kishikawa, Makoto Yamashita, Satoshi Koizumi, Takashi Kurakawa, Ryu Okumura, Hisako Kayama, Mari Murakami, Taiki Sakaguchi, Bhabatosh Das, Shota Nakamura, Yukinori Okada, Atsushi Kumanogoh, Kiyoshi Takeda
Journal: Annals of the Rheumatic Diseases (2023)

Objectives Prevotella copri is considered to be a contributing factor in rheumatoid arthritis (RA). However, in some non-Westernised countries, healthy individuals also harbour an abundance of P. copri in the intestine. This study investigated the pathogenicity of RA patient-derived P. copri ( P. copri RA ) compared with healthy control-derived P. copri ( P. copri HC ). Methods We obtained 13 P . copri strains from the faeces of patients with RA and healthy controls. Following whole genome sequencing, the sequences of P. copri RA and P. copri HC were compared. To analyse the arthritis-inducing ability of P. copri , we examined two arthritis models (1) a collagen-induced arthritis model harbouring P. copri under specific-pathogen-free conditions and (2) an SKG mouse arthritis model under P. copri -monocolonised conditions. Finally, to evaluate the ability of P. copri to activate innate immune cells, we performed in vitro stimulation of bone marrow-derived dendritic cells (BMDCs) by P. copri RA and P. copri HC . Results Comparative genomic analysis revealed no apparent differences in the core gene contents between P. copri RA and P. copri HC , but pangenome analysis revealed the high genome plasticity of P. copri . We identified a P. copri RA -specific genomic region as a conjugative transposon. In both arthritis models, P. copri RA -induced more severe arthritis than P. copri HC . In vitro BMDC stimulation experiments revealed the upregulation of IL-17 and Th17-related cytokines (IL-6, IL-23) by P. copri RA . Conclusion Our findings reveal the genetic diversity of P. copri , and the genomic signatures associated with strong arthritis-inducing ability of P. copri RA . Our study contributes towards elucidation of the complex pathogenesis of RA.
GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology
Authors: Zachary M. Earley, Wioletta Lisicka, Joseph J. Sifakis, Raúl Aguirre-Gamboa, Anita Kowalczyk, Jacob T. Barlow, Dustin G. Shaw, Valentina Discepolo, Ineke L. Tan, Saideep Gona, Jordan D. Ernest, Polly Matzinger, Luis B. Barreiro, Andrey Morgun, Albert Bendelac, Rustem F. Ismagilov, Natalia Shulzhenko, Samantha J. Riesenfeld, Bana Jabri
Journal: Immunity (2023)
T cell-derived interleukin-22 drives the expression of CD155 by cancer cells to suppress NK cell function and promote metastasis
Authors: Daria Briukhovetska, Javier Suarez-Gosalvez, Cornelia Voigt, Anamarija Markota, Anastasios D Giannou, Maryam Schübel, Jakob Jobst, Tao Zhang, Janina Dörr, Florian Märkl, Lina Majed, Philipp Jie Müller, Peter May, Adrian Gottschlich, Nicholas Tokarew, Jöran Lücke, Arman Oner, Melanie Schwerdtfeger, David Andreu-Sanz, Ruth Grünmeier, Matthias Seifert, Stefanos Michaelides, Michael Hristov, Lars M König, Bruno Loureiro Cadilha, Oleg Mikhaylov, Hans-Joachim Anders, Simon Rothenfusser, Richard A Flavell, Daniela Cerezo-Wallis, Cristina Tejedo, María S Soengas, Tobias Bald, Samuel Huber, Stefan Endres, Sebastian Kobold
Journal: Immunity (2023)
The 1/4/6x24 campaign to cure tuberculosis quickly
Authors: Lindsay McKenna, Mike Frick, Ketholelie Angami, Vuyiseka Dubula, Jennifer Furin, Mark Harrington, Harry Hausler, Petra Heitkamp, Rosa Herrera, Sharonann Lynch, Carole D. Mitnick, Gloriah Kerubo Moses, Norbert Ndjeka, Bern-Thomas Nyang’wa, Lindsay Palazuelos, Patrick Ulysse, Madhukar Pai
Journal: Nature Medicine (2023)
Late-onset enteric virus infection associated with hepatitis (EVAH) in transplanted SCID patients
Authors: Quentin Riller, Jacques Fourgeaud, Julie Bruneau, Suk See De Ravin, Grace Smith, Mathieu Fusaro, Samy Meriem, Aude Magerus, Marine Luka, Ghaith Abdessalem, Ludovic Lhermitte, Anne Jamet, Emmanuelle Six, Alessandra Magnani, Martin Castelle, Romain Lévy, Mathilde M. Lecuit, Benjamin Fournier, Sarah Winter, Michaela Semeraro, Graziella Pinto, Hanène Abid, Nizar Mahlaoui, Nathalie Cheikh, Benoit Florkin, Pierre Frange, Eric Jeziorski, Felipe Suarez, Françoise Sarrot-Reynauld, Dalila Nouar, Dominique Debray, Florence Lacaille, Capucine Picard, Philippe Pérot, Béatrice Regnault, Nicolas Da Rocha, Camille de Cevins, Laure Delage, Brieuc P. Pérot, Angélique Vinit, Francesco Carbone, Camille Brunaud, Manon Marchais, Marie-Claude Stolzenberg, Vahid Asnafi, Thierry Molina, Frédéric Rieux-Laucat, Luigi D. Notarangelo, Stefania Pittaluga, Jean Philippe Jais, Despina Moshous, Stephane Blanche, Harry Malech, Marc Eloit, Marina Cavazzana, Alain Fischer, Mickaël M. Ménager, Bénédicte Neven
Journal: Journal of Allergy and Clinical Immunology (2023)
Biodegradable silica nanocapsules enable efficient nuclear-targeted delivery of native proteins for cancer therapy
Authors: Wei Du, Shubo Du, Xiao Dong, Hua Bai, Jiamin Jiang, Shiping Hao, Fen Yang, Qicai Xiao, Bei Zhang, Jingyan Ge, Liqian Gao, Lin Li, Shao Q. Yao, Wei Huang
Journal: Biomaterials (2023)
Crosstalk between 5-methylcytosine and N6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma
Authors: Yu Tian, Haijuan Xiao, Yanhui Yang, Pingping Zhang, Jiahui Yuan, Wei Zhang, Lijie Chen, Yibao Fan, Jinze Zhang, Huan Cheng, Tingwei Deng, Lin Yang, Weiwei Wang, Guoyong Chen, Peiqin Wang, Peng Gong, Xing Niu, Xianbin Zhang
Journal: Molecular Cancer (2023)

Accumulated evidence highlights the significance of the crosstalk between epigenetic and epitranscriptomic mechanisms, notably 5-methylcytosine (5mC) and N6-methyladenosine (m6A). Herein, we conducted a widespread analysis regarding the crosstalk between 5mC and m6A regulators in hepatocellular carcinoma (HCC).Pan-cancer genomic analysis of the crosstalk between 5mC and m6A regulators was presented at transcriptomic, genomic, epigenetic, and other multi-omics levels. Hub 5mC and m6A regulators were summarized to define an epigenetic and epitranscriptomic module eigengene (EME), which reflected both the pre- and post-transcriptional modifications.5mC and m6A regulators interacted with one another at the multi-omic levels across pan-cancer, including HCC. The EME scoring system enabled to greatly optimize risk stratification and accurately predict HCC patients' clinical outcomes and progression. Additionally, the EME accurately predicted the responses to mainstream therapies (TACE and sorafenib) and immunotherapy as well as hyper-progression. In vitro, 5mC and m6A regulators cooperatively weakened apoptosis and facilitated proliferation, DNA damage repair, G2/M arrest, migration, invasion and epithelial-to-mesenchymal transition (EMT) in HCC cells. The EME scoring system was remarkably linked to potential extrinsic and intrinsic immune escape mechanisms, and the high EME might contribute to a reduced copy number gain/loss frequency. Finally, we determined potential therapeutic compounds and druggable targets (TUBB1 and P2RY4) for HCC patients with high EME.Our findings suggest that HCC may result from a unique synergistic combination of 5mC-epigenetic mechanism mixed with m6A-epitranscriptomic mechanism, and their crosstalk defines therapeutic response and pharmacogenomic landscape.
Environmental Impact of Prostate Magnetic Resonance Imaging and Transrectal Ultrasound Guided Prostate Biopsy
Authors: Michael S. Leapman, Cassandra L. Thiel, Ilyssa O. Gordon, Adam C. Nolte, Aaron Perecman, Stacy Loeb, Michael Overcash, Jodi D. Sherman
Journal: European Urology (2023)
Pervasive Selection for Clinically Relevant Resistance and Media Adaptive Mutations at Very Low Antibiotic Concentrations
Authors: Catia Pereira, Omar M Warsi, Dan I Andersson
Journal: Molecular Biology and Evolution (2023)

Abstract Experimental evolution studies have shown that weak antibiotic selective pressures (i.e., when the antibiotic concentrations are far below the minimum inhibitory concentration, MIC) can select resistant mutants, raising several unanswered questions. First, what are the lowest antibiotic concentrations at which selection for de novo resistance mutations can occur? Second, with weak antibiotic selections, which other types of adaptive mutations unrelated to the antibiotic selective pressure are concurrently enriched? Third, are the mutations selected under laboratory settings at subMIC also observed in clinical isolates? We addressed these questions using Escherichia coli populations evolving at subMICs in the presence of either of four clinically used antibiotics: fosfomycin, nitrofurantoin, tetracycline, and ciprofloxacin. Antibiotic resistance evolution was investigated at concentrations ranging from 1/4th to 1/2000th of the MIC of the susceptible strain (MICsusceptible). Our results show that evolution was rapid across all the antibiotics tested, and selection for fosfomycin- and nitrofurantoin-resistant mutants was observed at a concentration as low as 1/2000th of MICsusceptible. Several of the evolved resistant mutants showed increased growth yield and exponential growth rates, and outcompeted the susceptible ancestral strain in the absence of antibiotics as well, suggesting that adaptation to the growth environment occurred in parallel with the selection for resistance. Genomic analysis of the resistant mutants showed that several of the mutations selected under these conditions are also found in clinical isolates, demonstrating that experimental evolution at very low antibiotic levels can help in identifying novel mutations that contribute to bacterial adaptation during subMIC exposure in real-life settings.
Addressing the genetic/nongenetic duality in cancer with systems biology
Authors: Prakash Kulkarni, H. Steven Wiley, Herbert Levine, Herbert Sauro, Alexander Anderson, Stephen T.C. Wong, Aaron S. Meyer, Puneeth Iyengar, Kevin Corlette, Kristin Swanson, Atish Mohanty, Supriyo Bhattacharya, Amit Patel, Vinay Jain, Ravi Salgia
Journal: Trends in cancer (2023)
Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma
Authors: Pallawi Torka, Swetha Kambhampati Thiruvengadam, Lu Chen, Xiaoguang Wang, Canping Chen, Dan Vuong, Hanjun Qin, Alexandra Muir, Kirsten Orand, Ivana Borja, D. Lynne Smith, Alex F. Herrera, Stephen E. F. Spurgeon, Byung Park, Lionel D. Lewis, Francisco Hernandez-Ilizaliturri, Zheng Xia, Alexey V. Danilov
Journal: Blood Cancer Journal (2023)

Abstract Pevonedistat (TAK924) is a Nedd8-activating enzyme inhibitor with preclinical activity in non-Hodgkin lymphoma (NHL). This open-label, Phase I, multicenter, investigator-sponsored study enrolled patients with relapsed/refractory (R/R) NHL and chronic lymphocytic leukemia (CLL). The primary objective was safety. Pevonedistat was given intravenously on days 1, 3, 5 of a 21-day cycle for 8 cycles at five dose levels (15 to 50 mg/m 2 ); ibrutinib was administered at 420 or 560 mg orally daily continuously. Eighteen patients with NHL were enrolled, including 8 patients with mantle cell lymphoma (MCL) and 4 patients with CLL. One dose-limiting toxicity (mediastinal hemorrhage) occurred at 50 mg/m 2 of pevonedistat which is the estimated maximum tolerated dose. Bruising and diarrhea were the most common adverse events (56% and 44%). Atrial fibrillation occurred in 3 patients (17%). Grade ≥3 toxicities included arthralgia, atrial fibrillation, bone pain, diarrhea, hypertension, and mediastinal hemorrhage (one patient each). The overall response rate (ORR) was 65% (100% ORR in MCL). Pevonedistat disposition was not modified by ibrutinib. scRNA-Seq analysis showed that pevonedistat downregulated NFκB signaling in malignant B-cells in vivo. Thus, pevonedistat combined with ibrutinib demonstrated safety and promising early efficacy in NHL and CLL. NAE inhibition downregulated NFκB signaling in vivo.
Sequre: a high-performance framework for secure multiparty computation enables biomedical data sharing
Authors: Haris Smajlović, Ariya Shajii, Bonnie Berger, Hyunghoon Cho, Ibrahim Numanagić
Journal: Genome biology (2023)

Abstract Secure multiparty computation (MPC) is a cryptographic tool that allows computation on top of sensitive biomedical data without revealing private information to the involved entities. Here, we introduce Sequre, an easy-to-use, high-performance framework for developing performant MPC applications. Sequre offers a set of automatic compile-time optimizations that significantly improve the performance of MPC applications and incorporates the syntax of Python programming language to facilitate rapid application development. We demonstrate its usability and performance on various bioinformatics tasks showing up to 3–4 times increased speed over the existing pipelines with 7-fold reductions in codebase sizes.
Dhx33 promotes B-cell growth and proliferation by controlling activation-induced rRNA upregulation
Authors: Xiaoyu He, Jiayi Zhao, Abidan Adilijiang, Peicheng Hong, Pengda Chen, Xinyong Lin, Jun Xie, Ying Du, Yun Liu, Lianghua Lin, Hyun Yong Jin, Yazhen Hong, Wen-Hsien Liu, Changchun Xiao
Journal: Cellular and Molecular Immunology (2023)